Harrison Distinguished Professor, Molecular Physiology and Biological Physics
- BS, Chemistry, Carnegie Mellon University
- Mphil, Molecular Biophysics, Yale University
- PhD, Molecular Biophysics, Yale University
- MD, Medicine, Yale University School of Medicine
Biophysics, Biotechnology, Cardiovascular Biology, Molecular Biology, Physiology, Structural Biology
Cardiac Gap Junction Membrane Channels / Integrins Water Channels / Rotavirus / Reovirus / Retrovirus
The ultimate goal of our studies is to gain a deeper understanding of the molecular basis for important human diseases such as sudden death, myocardial infarction, rotavirus infection and HIV infection that cause substantial mortality and suffering. The structural details revealed by our work may provide clues for the design of more effective and safer medicines.
At the basic science level, we are intrigued by biological questions at the interface between cell biology and structural biology. How do membrane channels open and close? How are signals transmitted across a cellular membrane when an extracellular ligand binds to a membrane receptor? How do viruses attach and enter host cells, replicate and assemble infectious particles?
In our laboratory we use high resolution electron cryo-microscopy (cryo-EM) and image processing to explore the molecular design of large, multicomponent supramolecular assemblies. Biological specimens are quick frozen in a physiological state to preserve their native structure and functional properties. A special advantage of this rapid-freezing method is that we can trap and image dynamic states of functioning macromolecular assemblies, such as open and closed states of membrane channels and viruses actively transcribing RNA. Three-dimensional density maps are obtained by digital image processing of the high-resolution electron micrographs. The rich detail in the maps reveals the structural organization of complex biological structures that can be related to the functional properties of such assemblies.
Research projects underway include the structure analysis of:
(1) Membrane proteins involved with cell-to-cell communication (gap junctions), water transport (aquaporins), ionic transport (potassium channels), transmembrane signaling (integrins), and viral recognition (rotavirus NSP4)
(2) RNA viruses responsible for significant human disease (rotavirus, astrovirus, retroviruses)
(3) RNA viruses used as model systems to understand mechanisms of pathogenesis (reovirus, nodaviruses, sobemoviruses, nudaurelia capensis omega Greek symbol virus, rice yellow mottle virus).
Restenosis after Coronary Artery Angioplasty and Stent Placement:
Cardiovascular disease is the major cause of mortality in the United States. Most of these deaths are due to myocardial infarction caused by coronary artery atherosclerosis. A recent advancement in the treatment of coronary atherosclerosis is percutaneous transluminal coronary angioplasty combined with implantation of a balloon-expandable stent, which acts as a metallic scaffold to maintain patency of the diseased vessel. An adverse consequence of this procedure, which usually occurs within 3-12 months, is a proliferation of cells in the wall of the artery, a process termed neointimal hyperplasia. In many patients, neointimal hyperplasia narrows the lumen of the vessel (i.e. causes restenosis) and results in impaired myocardial blood flow. The porcine in vivo coronary artery injury model most closely resembles the process of restenosis after stent placement in humans and therefore provides the best system for delineating the pathophysiology of neointimal hyperplasia. Oligonucleotide microarray technology provides unprecedented opportunities to understand and treat human disease. The pattern of mRNA abundance can be used to gain insight into the “molecular circuitry” of disease. In collaboration with Dr. Robert Russo at Scripps Clinic , we are using this technology to explore the molecular basis of restenosis. Our preliminary analysis suggests that levels of mRNA for several genes are dramatically changed. Identification of cell receptors and signaling pathways associated with stent-induced vascular injury in this porcine model may guide the design of novel treatments to prevent restenosis in humans.
List of Publications in Pubmed